Glomerular Filtration Rate Estimation Using ß2-Microglobulin and ß-Trace Protein in Adults With Solid Tumors: A Prospective Cross-Sectional Study.

RATIONALE & OBJECTIVE: ß2-Microglobulin (B2M) and ß-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFRcr-cys), but they have not been assessed in patients with cancer. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017. EXPOSURE: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR). OUTCOME: Performance of equations compared with eGFRcr-cys and non-GFR determinants of serum B2M and BTP (SB2M, and SBTP, respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). ANALYTICAL APPROACH: Bias was defined as the median of the differences between mGFR and eGFR, and 1-P30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P30). Linear regression was used to assess association of clinical and laboratory variables with SB2M, and SBTP after adjustment for mGFR. RESULTS: Mean age and mGFR were 58.8±13.2 SD years and 78.4±21.7 SD mL/min/1.73m2, respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys (lesser bias and 1-P30). Performance of 2-marker panel equations was as good as eGFRcr-cys (lesser bias and similar 1-P30). SB2M and SBTP were not strongly influenced by cancer site. LIMITATIONS: Participants may have had better clinical performance status than the general population of patients with solid tumors. CONCLUSIONS: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine. PLAIN-LANGUAGE SUMMARY: The most accurate method to assess estimate kidney function is estimated glomerular filtration rate (eGFR) using creatinine and cystatin C (eGFRcr-cys). We studied whether using ß2-microglobulin (B2M) and/or ß-trace protein (BTP) with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR) might be useful in patients with active solid tumors. The performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys. Performance of 2-marker panel equations was as good as eGFRcr-cys. We conclude that B2M and BTP can improve the accuracy of eGFR and may be useful as a confirmatory test in patients with solid tumors either by inclusion in multimarker panel equation with creatinine and cystatin C or by substituting for cystatin C in combination with creatinine.

A prospective cross-sectional study estimated glomerular filtration rate from creatinine and cystatin C in adults with solid tumors.

Current guidelines recommend estimating glomerular filtration rate (eGFR) using creatinine (eGFRcr) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation as the first test for GFR evaluation, but the Cockcroft-Gault (CG) equation is still commonly used in oncology practice and clinical trials despite increasing evidence of its inaccuracy compared to measured GFR (mGFR). Guidelines recommend eGFR using cystatin C (eGFRcys) or both markers (eGFRcr-cys) as a confirmatory test, but neither was carefully evaluated in cancer patients. Therefore, we compared performance of the CKD-EPI equations and others to the CG equation in adults with a variety of solid tumors. The mGFR was determined by plasma clearance of 51Cr-EDTA. Bias was defined as the median of the differences between mGFR and eGFR while accuracy was defined as the percentage of estimates that differed by more than 30% from the measured GFR (1-P30). We prospectively recruited 1,200 patients between April 2015 and September 2017 with a mean age and mGFR of 58.8 years and 78.4 ml/min/1.73m2, respectively. Bias among eGFRcr equations varied from -8.1 to +6.1 ml/min/1.73 m2. CG was the least accurate, 1-P30 (95% confidence interval) was 24.9 (22.4- 27.3)%; CKD-EPI had 1-P30 of 19.1 (16.8-21.2)% while eGFRcr-cys had the best performance: bias -2.0 (-2.6 to -1.1) ml/min/1.73m2 and 1-P30 7.8 (6.3-9.4)%. Thus, the CG equation should not be preferred over CKD-EPI equation, and eGFRcr-cys can be used as a confirmatory test in adults with solid tumors. Hence, a major policy implication would be to adopt general practice guideline-recommended methods for GFR evaluation in oncology practice and clinical trials.

Post-acute sequelae of SARS-CoV-2 infection: relationship of central nervous system manifestations with physical disability and systemic inflammation.

BACKGROUND: Despite the multitude of clinical manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC), studies applying statistical methods to directly investigate patterns of symptom co-occurrence and their biological correlates are scarce. METHODS: We assessed 30 symptoms pertaining to different organ systems in 749 adults (age = 55 ± 14 years; 47% female) during in-person visits conducted at 6-11 months after hospitalization due to coronavirus disease 2019 (COVID-19), including six psychiatric and cognitive manifestations. Symptom co-occurrence was initially investigated using exploratory factor analysis (EFA), and latent variable modeling was then conducted using Item Response Theory (IRT). We investigated associations of latent variable severity with objective indices of persistent physical disability, pulmonary and kidney dysfunction, and C-reactive protein and D-dimer blood levels, measured at the same follow-up assessment. RESULTS: The EFA extracted one factor, explaining 64.8% of variance; loadings were positive for all symptoms, and above 0.35 for 16 of them. The latent trait generated using IRT placed fatigue, psychiatric, and cognitive manifestations as the most discriminative symptoms (coefficients > 1.5, p < 0.001). Latent trait severity was associated with decreased body weight and poorer physical performance (coefficients > 0.240; p ⩽ 0.003), and elevated blood levels of C-reactive protein (coefficient = 0.378; 95% CI 0.215-0.541; p < 0.001) and D-dimer (coefficient = 0.412; 95% CI 0.123-0.702; p = 0.005). Results were similar after excluding subjects with pro-inflammatory comorbidities. CONCLUSIONS: Different symptoms that persist for several months after moderate or severe COVID-19 may unite within one latent trait of PASC. This trait is dominated by fatigue and psychiatric symptoms, and is associated with objective signs of physical disability and persistent systemic inflammation.

Association of magnesium abnormalities at intensive care unit admission with kidney outcomes and mortality: a prospective cohort study.

BACKGROUND: Magnesium abnormalities have been associated with adverse kidney outcomes and mortality in critically ill patients, however, this association remains inconsistent. This study aimed to investigate the association of magnesium abnormalities at intensive care unit (ICU) admission with kidney outcomes (i.e., acute kidney injury (AKI) and kidney function recovery) and mortality risk in a large cohort of critically ill patients. METHODS: A prospective cohort study was conducted by collecting data from three ICUs in Brazil. The ICU admission serum magnesium level was used to define hypomagnesemia (< 1.60 mg/dL) and hypermagnesemia (> 2.40 mg/dL). The Kidney Disease Improving Global Outcomes AKI Guideline was used to define AKI based on serum creatinine levels. Kidney function recovery was defined as full recovery, partial recovery, and non-recovery at ICU discharge. Mortality was screened up to 28 days during ICU stay. RESULTS: A total of 7,042 patients was analyzed, hypomagnesemia was found in 18.4% (n = 1,299) and hypermagnesemia in 4.4% (n = 311). Patients with hypomagnesemia were 25% more likely to develop AKI after adjustment for confounding variables (OR = 1.25; 95% CI 1.08-1.46). No significant association was found for hypermagnesemia and AKI (OR = 1.18; 95% CI 0.89-1.57). Kidney function recovery was similar among groups but hypermagnesemia had lower non-recovery rates. Both hypomagnesemia and hypermagnesemia were associated with 65 and 52% higher mortality risk after adjustments for confounders, respectively (HR = 1.65; 95% CI 1.32-2.06 and 1.52; 95% CI 1.01-2.29). CONCLUSIONS: Hypomagnesemia, but not hypermagnesemia, at ICU admission was associated with AKI development. On the other hand, both hypomagnesemia and hypermagnesemia were associated with higher mortality risks.

Medical students' and health professionals' knowledge regarding acute kidney injury: a cross-sectional study in the city of São Paulo, Brazil.

BACKGROUND: Acute kidney injury (AKI) is a worldwide public health problem and is often treated by non-nephrologists. The objective of this study was to evaluate the knowledge of non-nephrologists, undergraduate medical students and health professionals regarding AKI. METHODS: An unsupervised and closed-response electronic questionnaire was sent to sixth-year medical students and non-nephrologist health professionals working in the city of São Paulo, Brazil. RESULTS: A total of 424 responses were returned from 650 invitations (40.1% males, 39.2% physicians, 34.0% senior medical students or resident physicians, 16.3% nurses and 10.6% pharmacists). The knowledge of medical students and health professionals about the prevalence and lethality of AKI in hospitals ranged from 40.8% to 59.2%. The most recognized susceptibilities and risk factors for AKI were sepsis/septic shock (95.0%) and diabetes mellitus (91.3%); the less-recognized susceptibilities and risk factors were exposure to gadolinium-based contrast (23.3%) and chronic liver disease (55.7%). The study participants' rate of knowledge regarding the diagnosis of AKI was 50.9-73.6%, and their rate of knowledge regarding the criteria of increased serum creatinine and reduced urine volume was 52.6%. The most-recognized nephrotoxic medications were vancomycin (82.3%) and diclofenac (80.4%), and the least-recognized were acyclovir (34.0%) and cotrimoxazole (30.4%). The indications for emergency renal replacement therapy that were recognized by the study respondents were metabolic acidosis (82.3%), uremic syndrome (81.6%), hyperkalemia unresponsive to clinical treatment (78.1%) and acute pulmonary edema (71.6%). CONCLUSION: The study showed knowledge gaps that can impact patient care and can be used to guide professional training programs.

Recognition and management of community-acquired acute kidney injury in low-resource settings in the ISN 0by25 trial: A multi-country feasibility study.

BACKGROUND: Acute kidney injury (AKI) is increasingly encountered in community settings and contributes to morbidity, mortality, and increased resource utilization worldwide. In low-resource settings, lack of awareness of and limited access to diagnostic and therapeutic interventions likely influence patient management. We evaluated the feasibility of the use of point-of-care (POC) serum creatinine and urine dipstick testing with an education and training program to optimize the identification and management of AKI in the community in 3 low-resource countries. METHODS AND FINDINGS: Patients presenting to healthcare centers (HCCs) from 1 October 2016 to 29 September 2017 in the cities Cochabamba, Bolivia; Dharan, Nepal; and Blantyre, Malawi, were assessed utilizing a symptom-based risk score to identify patients at moderate to high AKI risk. POC testing for serum creatinine and urine dipstick at enrollment were utilized to classify these patients as having chronic kidney disease (CKD), acute kidney disease (AKD), or no kidney disease (NKD). Patients were followed for a maximum of 6 months with repeat POC testing. AKI development was assessed at 7 days, kidney recovery at 1 month, and progression to CKD and mortality at 3 and 6 months. Following an observation phase to establish baseline data, care providers and physicians in the HCCs were trained with a standardized protocol utilizing POC tests to evaluate and manage patients, guided by physicians in referral hospitals connected via mobile digital technology. We evaluated 3,577 patients, and 2,101 were enrolled: 978 in the observation phase and 1,123 in the intervention phase. Due to the high number of patients attending the centers daily, it was not feasible to screen all patients to assess the actual incidence of AKI. Of enrolled patients, 1,825/2,101 (87%) were adults, 1,117/2,101 (53%) were females, 399/2,101 (19%) were from Bolivia, 813/2,101 (39%) were from Malawi, and 889/2,101 (42%) were from Nepal. The age of enrolled patients ranged from 1 month to 96 years, with a mean of 43 years (SD 21) and a median of 43 years (IQR 27-62). Hypertension was the most common comorbidity (418/2,101; 20%). At enrollment, 197/2,101 (9.4%) had CKD, and 1,199/2,101 (57%) had AKD. AKI developed in 30% within 7 days. By 1 month, 268/978 (27%) patients in the observation phase and 203/1,123 (18%) in the intervention phase were lost to follow-up. In the intervention phase, more patients received fluids (observation 714/978 [73%] versus intervention 874/1,123 [78%]; 95% CI 0.63, 0.94; p = 0.012), hospitalization was reduced (observation 578/978 [59%] versus intervention 548/1,123 [49%]; 95% CI 0.55, 0.79; p < 0.001), and admitted patients with severe AKI did not show a significantly lower mortality during follow-up (observation 27/135 [20%] versus intervention 21/178 [11.8%]; 95% CI 0.98, 3.52; p = 0.057). Of 504 patients with kidney function assessed during the 6-month follow-up, de novo CKD arose in 79/484 (16.3%), with no difference between the observation and intervention phase (95% CI 0.91, 2.47; p = 0.101). Overall mortality was 273/2,101 (13%) and was highest in those who had CKD (24/106; 23%), followed by those with AKD (128/760; 17%), AKI (85/628; 14%), and NKD (36/607; 6%). The main limitation of our study was the inability to determine the actual incidence of kidney dysfunction in the health centers as it was not feasible to screen all the patients due to the high numbers seen daily. CONCLUSIONS: This multicenter, non-randomized feasibility study in low-resource settings demonstrates that it is feasible to implement a comprehensive program utilizing POC testing and protocol-based management to improve the recognition and management of AKI and AKD in high-risk patients in primary care.

Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address.

Expansive Vascular Remodeling and Increased Vascular Calcification Response to Cholecalciferol in a Murine Model of Obesity and Insulin Resistance.

Objective- We hypothesized that ob/ob mice develop expansive vascular remodeling associated with calcification. Approach and Results- We quantified and investigated mechanisms of vascular remodeling and vascular calcification in ob/ob mice after vitamin D3(VD) stimulation or PBS (control), compared with C57BL/6 mice. Both ob/ob (OBVD [VD-treated ob/ob mice]) and C57BL/6 (C57VD [VD-treated C57BL/6 mice]) received 8×103 IU/day of intraperitoneal VD for 14 days. Control ob/ob (OBCT [PBS-treated ob/ob mice]) and C57BL/6 (C57CT [PBS-treated C57BL/6 mice]) received intraperitoneal PBS for 14 days. Hypervitaminosis D increased the external and internal elastic length in aortae from OBVD, resulting in increased total vascular area and lumen vascular area, respectively, which characterizes expansive vascular remodeling. OBVD decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increased collagen deposition, elastolysis, and calcification in aortae from OBVD. Our results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD. We demonstrated increased serum calcium levels, augmented Bmp (bone morphogenetic protein)-2 and osteochondrogenic proteins expression in OBVD aortae. Furthermore, aortae from OBVD increased oxidative stress, coincidently with augmented in situ MMP (matrix metalloproteinase) activity and exhibited no VDR (VD receptor) inhibition after VD. Conclusions- Our data provide evidence that obese and insulin-resistant mice (ob/ob) developed expansive hypotrophic vascular remodeling correlated directly with increased vascular calcification after chronic VD stimulation. Positive hypotrophic vascular remodeling and vascular calcification in this mouse model is possibly mediated by the convergence of absence VDR downregulation after VD stimulation, increased reactive oxygen species generation, and MMP activation.

Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

RATIONALE & OBJECTIVE: Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes. STUDY DESIGN: Post hoc analysis of a randomized controlled trial. SETTING & PARTICIPANTS: Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). EXPOSURE: Randomized treatment assignment (darbepoetin vs placebo). OUTCOMES: All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation. ANALYTICAL APPROACH: Proportional hazards regression. RESULTS: Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7). LIMITATIONS: Post hoc analyses of a subgroup of study participants. CONCLUSIONS: Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation.

Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease.

AIMS: Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis. MATERIALS AND METHODS: All-cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non-users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non-users and in multivariable proportional hazards models. RESULTS: There were 591 individuals who used metformin at baseline and 3447 non-users. Among propensity-matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non-users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all-cause mortality (HR, 0.49; 95% CI, 0.36-0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32-0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51-0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61-0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65-1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed. CONCLUSIONS: Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.

Acute kidney injury due to tropical infectious diseases and animal venoms: a tale of 2 continents.

South and Southeast Asia and Latin American together comprise 46 countries and are home to approximately 40% of the world population. The sociopolitical and economic heterogeneity, tropical climate, and malady transitions characteristic of the region strongly influence disease behavior and health care delivery. Acute kidney injury epidemiology mirrors these inequalities. In addition to hospital-acquired acute kidney injury in tertiary care centers, these countries face a large preventable burden of community-acquired acute kidney injury secondary to tropical infectious diseases or animal venoms, affecting previously healthy young individuals. This article reviews the epidemiology, clinical picture, prevention, risk factors, and pathophysiology of acute kidney injury associated with tropical diseases (malaria, dengue, leptospirosis, scrub typhus, and yellow fever) and animal venom (snakes, bees, caterpillars, spiders, and scorpions) in tropical regions of Asia and Latin America, and discusses the potential future challenges due to emerging issues.

Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study.

BACKGROUND: Epidemiological data for acute kidney injury are scarce, especially in low-income countries (LICs) and lower-middle-income countries (LMICs). We aimed to assess regional differences in acute kidney injury recognition, management, and outcomes. METHODS: In this multinational cross-sectional study, 322 physicians from 289 centres in 72 countries collected prospective data for paediatric and adult patients with confirmed acute kidney injury in hospital and non-hospital settings who met criteria for acute kidney injury. Signs and symptoms at presentation, comorbidities, risk factors for acute kidney injury, and process-of-care data were obtained at the start of acute kidney injury, and need for dialysis, renal recovery, and mortality recorded at 7 days, and at hospital discharge or death, whichever came earlier. We classified countries into high-income countries (HICs), upper-middle-income countries (UMICs), and combined LICs and LMICs (LLMICs) according to their 2014 gross national income per person. FINDINGS: Between Sept 29 and Dec 7, 2014, data were collected from 4018 patients. 2337 (58%) patients developed community-acquired acute kidney injury, with 889 (80%) of 1118 patients in LLMICs, 815 (51%) of 1594 in UMICs, and 663 (51%) of 1241 in HICs (for HICs vs UMICs p=0.33; p<0.0001 for all other comparisons). Hypotension (1615 [40%] patients) and dehydration (1536 [38%] patients) were the most common causes of acute kidney injury. Dehydration was the most frequent cause of acute kidney injury in LLMICs (526 [46%] of 1153 vs 518 [32%] of 1605 in UMICs vs 492 [39%] of 1260 in HICs) and hypotension in HICs (564 [45%] of 1260 vs 611 [38%%] of 1605 in UMICs vs 440 [38%] of 1153 LLMICs). Mortality at 7 days was 423 (11%) of 3855, and was higher in LLMICs (129 [12%] of 1076) than in HICs (125 [10%] of 1230) and UMICs (169 [11%] of 1549). INTERPRETATION: We identified common aetiological factors across all countries, which might be amenable to a standardised approach for early recognition and treatment of acute kidney injury. Study limitations include a small number of patients from outpatient settings and LICs, potentially under-representing the true burden of acute kidney injury in these areas. Additional strategies are needed to raise awareness of acute kidney injury in community health-care settings, especially in LICs. FUNDING: International Society of Nephrology.

ESRD After Heart Failure, Myocardial Infarction, or Stroke in Type 2 Diabetic Patients With CKD.

BACKGROUND: How cardiovascular (CV) events affect progression to end-stage renal disease (ESRD), particularly in the setting of type 2 diabetes, remains uncertain. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 4,022 patients with type 2 diabetes, anemia, and chronic kidney disease from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). PREDICTOR: Postrandomization CV events. OUTCOMES: ESRD (defined as initiation of dialysis for >30 days, kidney transplantation, or refusal or nonavailability of renal replacement therapy) and post-ESRD mortality within 30 days and during overall follow-up after an intercurrent CV event. LIMITATIONS: Population limited to clinical trial participants with diabetes and anemia. RESULTS: 155 of 652 (23.8%) ESRD cases occurred after an intercurrent CV event; 110 (16.9%) cases followed heart failure, 28 (4.3%) followed myocardial infarction, 12 (1.84%) followed stroke, and 5 (0.77%) followed multiple CV events. ESRD rate was higher within 30 days in individuals with an intercurrent CV event compared with those without an intercurrent event (HR, 22.2; 95% CI, 17.0-29.0). Compared to no intercurrent CV events, relative risks for ESRD were higher after the occurrence of heart failure overall (HR, 3.4; 95% CI, 2.7-4.2) and at 30 days (HR, 20.1; 95% CI, 14.5-27.9) than after myocardial infarction or stroke (P<0.001). Compared with individuals without pre-ESRD events, those with ESRD following intercurrent CV events were older, were more likely to have prior CV disease, and had higher (24.4 vs 23.1mL/min/1.73m2; P=0.01) baseline estimated glomerular filtration rates (eGFRs) and higher eGFRs at last measurement before ESRD (18.6 vs 15.2mL/min/1.73m2; P<0.001), whereas race, sex, and medication use were similar. Post-ESRD mortality was similar (P=0.3) with and without preceding CV events. CONCLUSIONS: Most ESRD cases occurred in individuals without intercurrent CV events who had lower eGFRs than individuals with intercurrent CV events, but similar post-ESRD mortality. Nevertheless, intercurrent CV events, particularly heart failure, are strongly associated with risk for ESRD. These findings underscore the need for kidney-specific therapies in addition to treatment of CV risk factors to lower ESRD incidence in diabetes.

Change in Hemoglobin Trajectory and Darbepoetin Dose Approaching End-Stage Renal Disease: Data from the Trial to Reduce Cardiovascular Events with Aranesp Therapy Trial.

BACKGROUND: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). METHODS: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD. RESULTS: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI -1.26 to -1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 µg/L and 20%, respectively. CONCLUSIONS: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1-2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP.

Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup.

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning.

C-Reactive Protein and Risk of ESRD: Results From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BACKGROUND: To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). STUDY DESIGN: Post hoc analysis of a randomized controlled trial. SETTING & PARTICIPANTS: 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. PREDICTOR: Baseline serum CRP concentrations. OUTCOMES: The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. MEASUREMENTS: We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. RESULTS: Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0mg/L, those with moderately/markedly elevated CRP levels (≥6.9mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. LIMITATIONS: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. CONCLUSIONS: Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD.